Abstract
Emerging evidence reveals enrichment of glioma-initiating cells (GICs) following therapeutic intervention. One factor known to contribute to this enrichment is cellular plasticity—the ability of glioma cells to attain multiple phenotypes. To elucidate the molecular mechanisms governing therapy-induced cellular plasticity, we performed genome-wide chromatin immunoprecipitation sequencing (ChIP-Seq) and gene expression analysis (gene microarray analysis) during treatment with standard of care temozolomide (TMZ) chemotherapy. Analysis revealed significant enhancement of open-chromatin marks in known astrocytic enhancers for interleukin-8 (IL-8) loci as well as elevated expression during anti-glioma chemotherapy. The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project data demonstrated that IL-8 transcript expression is negatively correlated with GBM patient survival (p = 0.001) and positively correlated with that of genes associated with the GIC phenotypes, such as KLF4, c-Myc, and HIF2α (p < 0.001). Immunohistochemical analysis of patient samples demonstrated elevated IL-8 expression in about 60% of recurrent GBM tumors relative to matched primary tumors and this expression also positively correlates with time to recurrence. Exposure to IL-8 significantly enhanced the self-renewing capacity of PDX GBM (average threefold, p < 0.0005), as well as increasing the expression of GIC markers in the CXCR2 population. Furthermore, IL-8 knockdown significantly delayed PDX GBM tumor growth in vivo (p < 0.0005). Finally, guided by in silico analysis of TCGA data, we examined the effect of therapy-induced IL-8 expression on the epigenomic landscape of GBM cells and observed increased trimethylation of H3K9 and H3K27. Our results show that autocrine IL-8 alters cellular plasticity and mediates alterations in histone status. These findings suggest that IL-8 signaling participates in regulating GBM adaptation to therapeutic stress and therefore represents a promising target for combination with conventional chemotherapy in order to limit GBM recurrence.
Highlights
Glioblastoma (GBM) is the most aggressive and prevalent primary brain tumor in adults, with 10,000 new diagnoses each year
To investigate if Temozolomide (TMZ) chemotherapy promotes the adoption of a Glioma-initiating cells (GICs) state via cellular plasticity, gene set enrichment analysis (GSEA) using the Affymetrix platform was performed
Dotted lines represent the edge of the tumor based on cell density and morphology. e–f patient-derived xenograft (PDX) GBM xenografts were harvested and immediately plated in either mild differentiation media (DMEM containing 1% fetal bovine serum (FBS)) or GIC maintenance media
Summary
Glioblastoma (GBM) is the most aggressive and prevalent primary brain tumor in adults, with 10,000 new diagnoses each year. With increased invasive and resistance capacities, are an inevitability for GBM patients despite aggressive therapeutic intervention. Glioma-initiating cells (GICs) are considered a key driver of primary tumor development, as well as major contributors to tumor recurrence[1]. Recent reports demonstrate that differentiated GBM cells undergo cellular and molecular changes to acquire GIC-like states[2,3]. This cellular plasticity dramatically complicates our ability to prevent tumor recurrence in the clinical setting. Our group and others have shown that therapeutic stress and microenvironmental dynamics induce cellular plasticity in GBM, driving the conversion of differentiated GBM cells to GIC states[3,4,5].
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